Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

TMR – This dates from December 2020. In the particular Montserrat context: Should not the relevant authorities be explaining the information that helps encourage persons access the vaccine, rather than reaching the point of wanting to shut those down who address the issues negatively, to making the vaccine mandatory?

List of authors.

  • Fernando P. Polack, M.D., Stephen J. Thomas, M.D., Nicholas Kitchin, M.D., Judith Absalon, M.D., Alejandra Gurtman, M.D., Stephen Lockhart, D.M., John L. Perez, M.D., Gonzalo Pérez Marc, M.D.,
  • Edson D. Moreira, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc.,
  • Kena A. Swanson, Ph.D., Satrajit Roychoudhury, Ph.D., Kenneth Koury, Ph.D., Ping Li, Ph.D., Warren V. Kalina, Ph.D., David Cooper, Ph.D.,
  • Robert W. Frenck, Jr., M.D., Laura L. Hammitt, M.D., Özlem Türeci, M.D., Haylene Nell, M.D., Axel Schaefer, M.D., Serhat Ünal, M.D.,
  • Dina B. Tresnan, D.V.M., Ph.D., Susan Mather, M.D., Philip R. Dormitzer, M.D., Ph.D., Uğur Şahin, M.D., Kathrin U. Jansen, Ph.D.,
  • and William C. Gruber, M.D. for the C4591001 Clinical Trial Group*

Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.

Methods

In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary endpoints were the efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.

Results

A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

Conclusions

A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728. opens in new tab.)

QUICK TAKESafety and Efficacy of the BNT162b2 Covid-19 Vaccine 03:00

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Coronavirus disease 2019 (Covid-19) has affected tens of millions of people globally1 since it was declared a pandemic by the World Health Organization on March 11, 2020.2 Older adults, persons with certain coexisting conditions, and front-line workers are at highest risk for Covid-19 and its complications. Recent data show increasing rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and Covid-19 in other populations, including younger adults.3 Safe and effective prophylactic vaccines are urgently needed to contain the pandemic, which has had devastating medical, economic, and social consequences.

We previously reported phase 1 safety and immunogenicity results from clinical trials of the vaccine candidate BNT162b2,4 a lipid nanoparticle–formulated,5 nucleoside-modified RNA (modRNA)6 encoding the SARS-CoV-2 full-length spike, modified by two proline mutations to lock it in the prefusion conformation.7 Findings from studies conducted in the United States and Germany among healthy men and women showed that two 30-μg doses of BNT162b2 elicited high SARS-CoV-2 neutralizing antibody titers and robust antigen-specific CD8+ and Th1-type CD4+ T-cell responses.8 The 50% neutralizing geometric mean titers elicited by 30 μg of BNT162b2 in older and younger adults exceeded the geometric mean titer measured in a human convalescent serum panel, despite a lower neutralizing response in older adults than in younger adults. In addition, the reactogenicity profile of BNT162b2 represented mainly short-term local (i.e., injection site) and systemic responses. These findings supported the progression of the BNT162b2 vaccine candidate into phase 3.

Here, we report safety and efficacy findings from the phase 2/3 part of a global phase 1/2/3 trial evaluating the safety, immunogenicity, and efficacy of 30 μg of BNT162b2 in preventing Covid-19 in persons 16 years of age or older. This data set and these trial results are the basis for an application for emergency use authorization.9 Collection of phase 2/3 data on vaccine immunogenicity and the durability of the immune response to immunization is ongoing, and those data are not reported here.

Methods

Trial Objectives, Participants, and Oversight

We assessed the safety and efficacy of two 30-μg doses of BNT162b2, administered intramuscularly 21 days apart, as compared with placebo. Adults 16 years of age or older who were healthy or had stable chronic medical conditions, including but not limited to human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus infection, were eligible for participation in the trial. Key exclusion criteria included a medical history of Covid-19, treatment with immunosuppressive therapy, or diagnosis with an immunocompromising condition.

Pfizer was responsible for the design and conduct of the trial, data collection, data analysis, data interpretation, and the writing of the manuscript. BioNTech was the sponsor of the trial, manufactured the BNT162b2 clinical trial material, and contributed to the interpretation of the data and the writing of the manuscript. All the trial data were available to all the authors, who vouch for its accuracy and completeness and for adherence of the trial to the protocol, which is available with the full text of this article at NEJM.org. An independent data and safety monitoring board reviewed efficacy and unblinded safety data.

Trial Procedures

With the use of an interactive Web-based system, participants in the trial were randomly assigned in a 1:1 ratio to receive 30 μg of BNT162b2 (0.3 ml volume per dose) or saline placebo. Participants received two injections, 21 days apart, of either BNT162b2 or placebo, delivered in the deltoid muscle. Site staff who were responsible for safety evaluation and were unaware of group assignments observed participants for 30 minutes after vaccination for any acute reactions.

Safety

The primary endpoints of this trial were solicited, specific local or systemic adverse events, and use of antipyretic or pain medication within 7 days after the receipt of each dose of vaccine or placebo, as prompted by and recorded in an electronic diary in a subset of participants (the reactogenicity subset), and unsolicited adverse events (those reported by the participants without prompts from the electronic diary) through 1 month after the second dose and unsolicited serious adverse events through 6 months after the second dose. Adverse event data through approximately 14 weeks after the second dose are included in this report. In this report, safety data are reported for all participants who provided informed consent and received at least one dose of vaccine or placebo. Per protocol, safety results for participants infected with HIV (196 patients) will be analyzed separately and are not included here.

During the phase 2/3 portion of the study, a stopping rule for the theoretical concern of vaccine-enhanced disease was to be triggered if the one-sided probability of observing the same or a more unfavorable adverse severe case split (a split with a greater proportion of severe cases in vaccine recipients) was 5% or less, given the same true incidence for vaccine and placebo recipients. Alert criteria were to be triggered if this probability was less than 11%.

Efficacy

The first primary endpoint was the efficacy of BNT162b2 against confirmed Covid-19 with onset at least 7 days after the second dose in participants who had been without serologic or virologic evidence of SARS-CoV-2 infection up to 7 days after the second dose; the second primary endpoint was efficacy in participants with and participants without evidence of prior infection. Confirmed Covid-19 was defined according to the Food and Drug Administration (FDA) criteria as the presence of at least one of the following symptoms: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, the new loss of taste or smell, sore throat, diarrhea, or vomiting, combined with a respiratory specimen obtained during the symptomatic period or within 4 days before or after it that was positive for SARS-CoV-2 by nucleic acid amplification-based testing, either at the central laboratory or at a local testing facility (using a protocol-defined acceptable test).

Major secondary endpoints included the efficacy of BNT162b2 against severe Covid-19. Severe Covid-19 is defined by the FDA as confirmed Covid-19 with one of the following additional features: clinical signs at rest that are indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death. Details are provided in the protocol.

An explanation of the various denominator values for use in assessing the results of the trial is provided in Table S1 in the Supplementary Appendix, available at NEJM.org. In brief, the safety population includes persons 16 years of age or older; a total of 43,448 participants constituted the population of enrolled persons injected with the vaccine or placebo. The main safety subset as defined by the FDA, with a median of two months of follow-up as of October 9, 2020, consisted of 37,706 persons, and the reactogenicity subset consisted of 8183 persons. The modified intention-to-treat (mITT) efficacy population includes all age groups 12 years of age or older (43,355 persons; 100 participants who were 12 to 15 years of age contributed to person-time years but included no cases). The number of persons who could be evaluated for efficacy 7 days after the second dose and who had no evidence of prior infection was 36,523, and the number of persons who could be evaluated 7 days after the second dose with or without evidence of prior infection was 40,137.

Statistical Analysis

The safety analyses included all participants who received at least one dose of BNT162b2 or placebo. The findings are descriptive in nature and not based on formal statistical hypothesis testing. Safety analyses are presented as counts, percentages, and associated Clopper–Pearson 95% confidence intervals for local reactions, systemic events, and any adverse events after vaccination, according to terms in the Medical Dictionary for Regulatory Activities (MedDRA), version 23.1, for each vaccine group.

Analysis of the first primary efficacy endpoint included participants who received the vaccine or placebo as randomly assigned, had no evidence of infection within 7 days after the second dose, and had no major protocol deviations (the population that could be evaluated). Vaccine efficacy was estimated by 100×(1−IRR), where IRR is the calculated ratio of confirmed cases of Covid-19 illness per 1000 person-years of follow-up in the active vaccine group to the corresponding illness rate in the placebo group. The 95.0% credible interval for vaccine efficacy and the probability of vaccine efficacy greater than 30% were calculated with the use of a Bayesian beta-binomial model. The final analysis uses a success boundary of 98.6% for probability of vaccine efficacy greater than 30% to compensate for the interim analysis and to control the overall type 1 error rate at 2.5%. Moreover, primary and secondary efficacy endpoints are evaluated sequentially to control the familywise type 1 error rate at 2.5%. Descriptive analyses (estimates of vaccine efficacy and 95% confidence intervals) are provided for key subgroups.

Results

Participants

Figure 1.

Enrollment and Randomization.Table 1.
Demographic Characteristics of the Participants in the Main Safety Population.

Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (the United States, 130 sites; Argentina, 1; Brazil, 2; South Africa, 4; Germany, 6; and Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections: 21,720 received BNT162b2 and 21,728 received placebo (Figure 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting condition. The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2).

Safety

Local Reactogenicity

Figure 2.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group.

The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients. Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). The pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose; 66% after the second dose) than among younger participants (83% after the first dose; 78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction. In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days.

Systemic Reactogenicity

Systemic events were reported more often by younger vaccine recipients (16 to 55 years of age) than by older vaccine recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger vaccine recipients; 51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger vaccine recipients; 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less. Severe systemic events were reported in less than 2% of vaccine recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose.

Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger vaccine recipients and by 11% of older recipients. Only 0.2% of vaccine recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose. Two participants each in the vaccine and placebo groups reported temperatures above 40.0°C. Younger vaccine recipients were more likely to use antipyretic or pain medication (28% after dose 1; 45% after dose 2) than older vaccine recipients (20% after dose 1; 38% after dose 2), and placebo recipients were less likely (10 to 14%) than vaccine recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter.

Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose. No difference was noted between the BNT162b2 group and the placebo group.

Adverse Events

Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%). This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by vaccine recipients than by placebo recipients. Sixty-four vaccine recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial. Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the vaccine or placebo. No Covid-19–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of the vaccine.

Efficacy

Table 2.

Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.Table 3.

Efficacy of BNT162b2 against Covid-19 after the First Dose.
Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.Figure 3.

Among 36,523 participants who had no evidence of existing or prior SARS-CoV-2 infection, 8 cases of Covid-19 with onset at least 7 days after the second dose were observed among vaccine recipients and 162 among placebo recipients. This case split corresponds to 95.0% vaccine efficacy (95% confidence interval [CI], 90.3 to 97.6; Table 2). Among participants with and those without evidence of prior SARS CoV-2 infection, 9 cases of Covid-19 at least 7 days after the second dose were observed among vaccine recipients and 169 among placebo recipients, corresponding to 94.6% vaccine efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that vaccine efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4). Vaccine efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (vaccine efficacy, 94.6%; 95% CI, 68.7 to 99.9; case split: BNT162b2, 2 cases; placebo, 44 cases). Figure 3 shows cases of Covid-19 or severe Covid-19 with onset at any time after the first dose (mITT population) (additional data on severe Covid-19 are available in Table S5). Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a vaccine efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the vaccine, starting as soon as 12 days after the first dose.

Discussion

A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be safe and 95% effective against Covid-19. The vaccine met both primary efficacy endpoints, with more than a 99.99% probability of a true vaccine efficacy greater than 30%. These results met our prespecified success criteria, which were to establish a probability above 98.6% of true vaccine efficacy being greater than 30%, and greatly exceeded the minimum FDA criteria for authorization.9 Although the study was not powered to definitively assess efficacy by subgroup, the point estimates of efficacy for subgroups based on age, sex, race, ethnicity, body-mass index, or the presence of an underlying condition associated with a high risk of Covid-19 complications are also high. For all analyzed subgroups in which more than 10 cases of Covid-19 occurred, the lower limit of the 95% confidence interval for efficacy was more than 30%.

The cumulative incidence of Covid-19 cases over time among placebo and vaccine recipients begins to diverge by 12 days after the first dose, 7 days after the estimated median viral incubation period of 5 days,10 indicating the early onset of a partially protective effect of immunization. The study was not designed to assess the efficacy of a single-dose regimen. Nevertheless, in the interval between the first and second doses, the observed vaccine efficacy against Covid-19 was 52%, and in the first 7 days after dose 2, it was 91%, reaching full efficacy against disease with onset at least 7 days after dose 2. Of the 10 cases of severe Covid-19 that were observed after the first dose, only 1 occurred in the vaccine group. This finding is consistent with overall high efficacy against all Covid-19 cases. The severe case split provides preliminary evidence of vaccine-mediated protection against severe disease, alleviating many of the theoretical concerns over vaccine-mediated disease enhancement.11

The favorable safety profile observed during phase 1 testing of BNT162b24,8 was confirmed in the phase 2/3 portion of the trial. As in phase 1, reactogenicity was generally mild or moderate, and reactions were less common and milder in older adults than in younger adults. Systemic reactogenicity was more common and severe after the second dose than after the first dose, although local reactogenicity was similar after the two doses. Severe fatigue was observed in approximately 4% of BNT162b2 recipients, which is higher than that observed in recipients of some vaccines recommended for older adults.12 This rate of severe fatigue is also lower than that observed in recipients of another approved viral vaccine for older adults.13 Overall, reactogenicity events were transient and resolved within a couple of days after onset. Lymphadenopathy, which generally resolved within 10 days, is likely to have resulted from a robust vaccine-elicited immune response. The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).

This trial and its preliminary report have several limitations. With approximately 19,000 participants per group in the subset of participants with a median follow-up time of 2 months after the second dose, the study has more than 83% probability of detecting at least one adverse event, if the true incidence is 0.01%, but it is not large enough to detect less common adverse events reliably. This report includes 2 months of follow-up after the second dose of vaccine for half the trial participants and up to 14 weeks’ maximum follow-up for a smaller subset. Therefore, both the occurrence of adverse events more than 2 to 3.5 months after the second dose and more comprehensive information on the duration of protection remains to be determined. Although the study was designed to follow participants for safety and efficacy for 2 years after the second dose, given the high vaccine efficacy, ethical and practical barriers prevent following placebo recipients for 2 years without offering active immunization, once the vaccine is approved by regulators and recommended by public health authorities. Assessment of long-term safety and efficacy for this vaccine will occur, but it cannot be in the context of maintaining a placebo group for the planned follow-up period of 2 years after the second dose. These data do not address whether vaccination prevents asymptomatic infection; a serologic endpoint that can detect a history of infection regardless of whether symptoms were present (SARS-CoV-2 N-binding antibody) will be reported later. Furthermore, given the high vaccine efficacy and the low number of vaccine breakthrough cases, the potential establishment of a correlate of protection has not been feasible at the time of this report.

This report does not address the prevention of Covid-19 in other populations, such as younger adolescents, children, and pregnant women. Safety and immune response data from this trial after immunization of adolescents 12 to 15 years of age will be reported subsequently, and additional studies are planned to evaluate BNT162b2 in pregnant women, children younger than 12 years, and those in special risk groups, such as immunocompromised persons. Although the vaccine can be stored for up to 5 days at standard refrigerator temperatures once ready for use, very cold temperatures are required for shipping and longer storage. The current cold storage requirement may be alleviated by ongoing stability studies and formulation optimization, which may also be described in subsequent reports.

The data presented in this report have significance beyond the performance of this vaccine candidate. The results demonstrate that Covid-19 can be prevented by immunization, provide proof of concept that RNA-based vaccines are a promising new approach for protecting humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with a sufficient investment of resources. The development of BNT162b2 was initiated on January 10, 2020, when the SARS-CoV-2 genetic sequence was released by the Chinese Center for Disease Control and Prevention and disseminated globally by the GISAID (Global Initiative on Sharing All Influenza Data) initiative. This rigorous demonstration of safety and efficacy less than 11 months later provides a practical demonstration that RNA-based vaccines, which require only viral genetic sequence information to initiate development, are a major new tool to combat pandemics and other infectious disease outbreaks. The continuous phase 1/2/3 trial design may provide a model to reduce the protracted development timelines that have delayed the availability of vaccines against other infectious diseases of medical importance. In the context of the current, still expanding pandemic, the BNT162b2 vaccine, if approved, can contribute, together with other public health measures, to reducing the devastating loss of health, life, and economic and social well-being that has resulted from the global spread of Covid-19.

Supported by BioNTech and Pfizer.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Polack and Thomas contributed equally to this article.

This article was published on December 10, 2020, and updated on December 16, 2020, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank all the participants who volunteered for this study; and the members of the C4591001 data and safety monitoring board for their dedication and their diligent review of the data. We also acknowledge the contributions of the C4591001 Clinical Trial Group (see the Supplementary Appendix); Tricia Newell and Emily Stackpole (ICON, North Wales, PA) for editorial support funded by Pfizer; and the following Pfizer staff: Greg Adams, Negar Aliabadi, Mohanish Anand, Fred Angulo, Ayman Ayoub, Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen, Salim Bouguermouh, Donna Boyce, Sarah Burden, Andrea Cawein, Patrick Caubel, Darren Cowen, Kimberly Ann Cristall, Michael Cruz, Daniel Curcio, Gabriela Dávila, Carmel Devlin, Gokhan Duman, Niesha Foster, Maja Gacic, Luis Jodar, Stephen Kay, William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie-Pierre Hellio Le Graverand-Gastineau, Jacqueline Lowenberg, Rod MacKenzie, Robert Maroko, Jason McKinley, Tracey Mellelieu, Farheen Muzaffar, Brendan O’Neill, Jason Painter, Elizabeth Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick, Balaji Prabu Raja, Christine Rainey, Kellie Lynn Richardson, Elizabeth Rogers, Melinda Rottas, Charulata Sabharwal, Vilas Satishchandran, Harpreet Seehra, Judy Sewards, Helen Smith, David Swerdlow, Elisa Harkins Tull, Sarah Tweedy, Erica Weaver, John Wegner, Jenah West, Christopher Webber, David C. Whritenour, Fae Wooding, Emily Worobetz, Xia Xu, Nita Zalavadia, Liping Zhang, the Vaccines Clinical Assay Team, the Vaccines Assay Development Team, and all the Pfizer colleagues not named here who contributed to the success of this trial. We also acknowledge the contributions of the following staff at BioNTech: Corinna Rosenbaum, Christian Miculka, Andreas Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi, Martin Bexon, Eleni Lagkadinou, and Alexandra Kemmer-Brück; and the following staff at Polymun: Dietmar Katinger and Andreas Wagner.

Author Affiliations

From Fundacion INFANT (F.P.P.) and iTrials-Hospital Militar Central (G.P.M.), Buenos Aires; State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (J.A., A.G., K.A.S., K.K., W.V.K., D.C., P.R.D., K.U.J., W.C.G.) — both in New York; Vaccine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., P.L.) and Worldwide Safety, Safety Surveillance and Risk Management (S.M.), Pfizer, Collegeville, PA; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and Centro Paulista de Investigação Clinica, São Paulo (C.Z.) — both in Brazil; Global Product Development, Pfizer, Peapack, NJ (S.R.); Cincinnati Children’s Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health, Baltimore (L.L.H.); BioNTech, Mainz (ÖT., U.Ş.), and Medizentrum Essen Borbeck, Essen (A.S.) — both in Germany; Tiervlei Trial Centre, Karl Bremer Hospital, Cape Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety, Safety Surveillance and Risk Management, Pfizer, Groton, CT (D.B.T.).

Address reprint requests to Dr. Absalon at Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, or at judith.absalon@pfizer.com.

A complete list of investigators in the C4591001 Clinical Trial Group is provided in the Supplementary Appendix, available at NEJM.org.

Supplementary Material

ProtocolPDF4781KB
Supplementary AppendixPDF171KB
Disclosure FormsPDF559KB
Data Sharing StatementPDF71KB
Research SummaryPDF3161KB

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Citing Articles (954)

Letters
Figures/Media
  1. Download a PDF of the Research Summary.
  2. Figure 1. Enrollment and Randomization. The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.
  3. Table 1. Demographic Characteristics of the Participants in the Main Safety Population.*
  4. Figure 2. Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel A. Pain at the injection site was assessed according to the following scale: mild, does not interfere with activity; moderate, interferes with activity; severe, prevents daily activity; and grade 4, emergency department visit or hospitalization. Redness and swelling were measured according to the following scale: mild, 2.0 to 5.0 cm in diameter; moderate, >5.0 to 10.0 cm in diameter; severe, >10.0 cm in diameter; and grade 4, necrosis or exfoliative dermatitis (for redness) and necrosis (for swelling). Systemic events and medication use are shown in Panel B. Fever categories are designated in the key; medication use was not graded. Additional scales were as follows: fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild: does not interfere with activity; moderate: some interference with activity; or severe: prevents daily activity), vomiting (mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; or severe: requires intravenous hydration), and diarrhea (mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; or severe: 6 or more loose stools in 24 hours); grade 4 for all events indicated an emergency department visit or hospitalization. 𝙸 bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.
  5. Table 2. Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.*
  6. Table 3. Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.
  7. Figure 3. Efficacy of BNT162b2 against Covid-19 after the First Dose. Shown is the cumulative incidence of Covid-19 after the first dose (modified intention-to-treat population). Each symbol represents Covid-19 cases starting on a given day; filled symbols represent severe Covid-19 cases. Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point. The time period for Covid-19 case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for vaccine efficacy (VE) is derived according to the Clopper–Pearson method.

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A Moment with the Registrar of Lands

TMR – This dates from December 2020. In the particular Montserrat context: Should not the relevant authorities be explaining the information that helps encourage persons access the vaccine, rather than reaching the point of wanting to shut those down who address the issues negatively, to making the vaccine mandatory?

List of authors.

Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.

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Methods

In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary endpoints were the efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.

Results

A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

Conclusions

A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728. opens in new tab.)

QUICK TAKESafety and Efficacy of the BNT162b2 Covid-19 Vaccine 03:00

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Coronavirus disease 2019 (Covid-19) has affected tens of millions of people globally1 since it was declared a pandemic by the World Health Organization on March 11, 2020.2 Older adults, persons with certain coexisting conditions, and front-line workers are at highest risk for Covid-19 and its complications. Recent data show increasing rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and Covid-19 in other populations, including younger adults.3 Safe and effective prophylactic vaccines are urgently needed to contain the pandemic, which has had devastating medical, economic, and social consequences.

We previously reported phase 1 safety and immunogenicity results from clinical trials of the vaccine candidate BNT162b2,4 a lipid nanoparticle–formulated,5 nucleoside-modified RNA (modRNA)6 encoding the SARS-CoV-2 full-length spike, modified by two proline mutations to lock it in the prefusion conformation.7 Findings from studies conducted in the United States and Germany among healthy men and women showed that two 30-μg doses of BNT162b2 elicited high SARS-CoV-2 neutralizing antibody titers and robust antigen-specific CD8+ and Th1-type CD4+ T-cell responses.8 The 50% neutralizing geometric mean titers elicited by 30 μg of BNT162b2 in older and younger adults exceeded the geometric mean titer measured in a human convalescent serum panel, despite a lower neutralizing response in older adults than in younger adults. In addition, the reactogenicity profile of BNT162b2 represented mainly short-term local (i.e., injection site) and systemic responses. These findings supported the progression of the BNT162b2 vaccine candidate into phase 3.

Here, we report safety and efficacy findings from the phase 2/3 part of a global phase 1/2/3 trial evaluating the safety, immunogenicity, and efficacy of 30 μg of BNT162b2 in preventing Covid-19 in persons 16 years of age or older. This data set and these trial results are the basis for an application for emergency use authorization.9 Collection of phase 2/3 data on vaccine immunogenicity and the durability of the immune response to immunization is ongoing, and those data are not reported here.

Methods

Trial Objectives, Participants, and Oversight

We assessed the safety and efficacy of two 30-μg doses of BNT162b2, administered intramuscularly 21 days apart, as compared with placebo. Adults 16 years of age or older who were healthy or had stable chronic medical conditions, including but not limited to human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus infection, were eligible for participation in the trial. Key exclusion criteria included a medical history of Covid-19, treatment with immunosuppressive therapy, or diagnosis with an immunocompromising condition.

Pfizer was responsible for the design and conduct of the trial, data collection, data analysis, data interpretation, and the writing of the manuscript. BioNTech was the sponsor of the trial, manufactured the BNT162b2 clinical trial material, and contributed to the interpretation of the data and the writing of the manuscript. All the trial data were available to all the authors, who vouch for its accuracy and completeness and for adherence of the trial to the protocol, which is available with the full text of this article at NEJM.org. An independent data and safety monitoring board reviewed efficacy and unblinded safety data.

Trial Procedures

With the use of an interactive Web-based system, participants in the trial were randomly assigned in a 1:1 ratio to receive 30 μg of BNT162b2 (0.3 ml volume per dose) or saline placebo. Participants received two injections, 21 days apart, of either BNT162b2 or placebo, delivered in the deltoid muscle. Site staff who were responsible for safety evaluation and were unaware of group assignments observed participants for 30 minutes after vaccination for any acute reactions.

Safety

The primary endpoints of this trial were solicited, specific local or systemic adverse events, and use of antipyretic or pain medication within 7 days after the receipt of each dose of vaccine or placebo, as prompted by and recorded in an electronic diary in a subset of participants (the reactogenicity subset), and unsolicited adverse events (those reported by the participants without prompts from the electronic diary) through 1 month after the second dose and unsolicited serious adverse events through 6 months after the second dose. Adverse event data through approximately 14 weeks after the second dose are included in this report. In this report, safety data are reported for all participants who provided informed consent and received at least one dose of vaccine or placebo. Per protocol, safety results for participants infected with HIV (196 patients) will be analyzed separately and are not included here.

During the phase 2/3 portion of the study, a stopping rule for the theoretical concern of vaccine-enhanced disease was to be triggered if the one-sided probability of observing the same or a more unfavorable adverse severe case split (a split with a greater proportion of severe cases in vaccine recipients) was 5% or less, given the same true incidence for vaccine and placebo recipients. Alert criteria were to be triggered if this probability was less than 11%.

Efficacy

The first primary endpoint was the efficacy of BNT162b2 against confirmed Covid-19 with onset at least 7 days after the second dose in participants who had been without serologic or virologic evidence of SARS-CoV-2 infection up to 7 days after the second dose; the second primary endpoint was efficacy in participants with and participants without evidence of prior infection. Confirmed Covid-19 was defined according to the Food and Drug Administration (FDA) criteria as the presence of at least one of the following symptoms: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, the new loss of taste or smell, sore throat, diarrhea, or vomiting, combined with a respiratory specimen obtained during the symptomatic period or within 4 days before or after it that was positive for SARS-CoV-2 by nucleic acid amplification-based testing, either at the central laboratory or at a local testing facility (using a protocol-defined acceptable test).

Major secondary endpoints included the efficacy of BNT162b2 against severe Covid-19. Severe Covid-19 is defined by the FDA as confirmed Covid-19 with one of the following additional features: clinical signs at rest that are indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death. Details are provided in the protocol.

An explanation of the various denominator values for use in assessing the results of the trial is provided in Table S1 in the Supplementary Appendix, available at NEJM.org. In brief, the safety population includes persons 16 years of age or older; a total of 43,448 participants constituted the population of enrolled persons injected with the vaccine or placebo. The main safety subset as defined by the FDA, with a median of two months of follow-up as of October 9, 2020, consisted of 37,706 persons, and the reactogenicity subset consisted of 8183 persons. The modified intention-to-treat (mITT) efficacy population includes all age groups 12 years of age or older (43,355 persons; 100 participants who were 12 to 15 years of age contributed to person-time years but included no cases). The number of persons who could be evaluated for efficacy 7 days after the second dose and who had no evidence of prior infection was 36,523, and the number of persons who could be evaluated 7 days after the second dose with or without evidence of prior infection was 40,137.

Statistical Analysis

The safety analyses included all participants who received at least one dose of BNT162b2 or placebo. The findings are descriptive in nature and not based on formal statistical hypothesis testing. Safety analyses are presented as counts, percentages, and associated Clopper–Pearson 95% confidence intervals for local reactions, systemic events, and any adverse events after vaccination, according to terms in the Medical Dictionary for Regulatory Activities (MedDRA), version 23.1, for each vaccine group.

Analysis of the first primary efficacy endpoint included participants who received the vaccine or placebo as randomly assigned, had no evidence of infection within 7 days after the second dose, and had no major protocol deviations (the population that could be evaluated). Vaccine efficacy was estimated by 100×(1−IRR), where IRR is the calculated ratio of confirmed cases of Covid-19 illness per 1000 person-years of follow-up in the active vaccine group to the corresponding illness rate in the placebo group. The 95.0% credible interval for vaccine efficacy and the probability of vaccine efficacy greater than 30% were calculated with the use of a Bayesian beta-binomial model. The final analysis uses a success boundary of 98.6% for probability of vaccine efficacy greater than 30% to compensate for the interim analysis and to control the overall type 1 error rate at 2.5%. Moreover, primary and secondary efficacy endpoints are evaluated sequentially to control the familywise type 1 error rate at 2.5%. Descriptive analyses (estimates of vaccine efficacy and 95% confidence intervals) are provided for key subgroups.

Results

Participants

Figure 1.

Enrollment and Randomization.Table 1.
Demographic Characteristics of the Participants in the Main Safety Population.

Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (the United States, 130 sites; Argentina, 1; Brazil, 2; South Africa, 4; Germany, 6; and Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections: 21,720 received BNT162b2 and 21,728 received placebo (Figure 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting condition. The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2).

Safety

Local Reactogenicity

Figure 2.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group.

The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients. Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). The pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose; 66% after the second dose) than among younger participants (83% after the first dose; 78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction. In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days.

Systemic Reactogenicity

Systemic events were reported more often by younger vaccine recipients (16 to 55 years of age) than by older vaccine recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger vaccine recipients; 51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger vaccine recipients; 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less. Severe systemic events were reported in less than 2% of vaccine recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose.

Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger vaccine recipients and by 11% of older recipients. Only 0.2% of vaccine recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose. Two participants each in the vaccine and placebo groups reported temperatures above 40.0°C. Younger vaccine recipients were more likely to use antipyretic or pain medication (28% after dose 1; 45% after dose 2) than older vaccine recipients (20% after dose 1; 38% after dose 2), and placebo recipients were less likely (10 to 14%) than vaccine recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter.

Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose. No difference was noted between the BNT162b2 group and the placebo group.

Adverse Events

Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%). This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by vaccine recipients than by placebo recipients. Sixty-four vaccine recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial. Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the vaccine or placebo. No Covid-19–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of the vaccine.

Efficacy

Table 2.

Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.Table 3.

Efficacy of BNT162b2 against Covid-19 after the First Dose.
Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.Figure 3.

Among 36,523 participants who had no evidence of existing or prior SARS-CoV-2 infection, 8 cases of Covid-19 with onset at least 7 days after the second dose were observed among vaccine recipients and 162 among placebo recipients. This case split corresponds to 95.0% vaccine efficacy (95% confidence interval [CI], 90.3 to 97.6; Table 2). Among participants with and those without evidence of prior SARS CoV-2 infection, 9 cases of Covid-19 at least 7 days after the second dose were observed among vaccine recipients and 169 among placebo recipients, corresponding to 94.6% vaccine efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that vaccine efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4). Vaccine efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (vaccine efficacy, 94.6%; 95% CI, 68.7 to 99.9; case split: BNT162b2, 2 cases; placebo, 44 cases). Figure 3 shows cases of Covid-19 or severe Covid-19 with onset at any time after the first dose (mITT population) (additional data on severe Covid-19 are available in Table S5). Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a vaccine efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the vaccine, starting as soon as 12 days after the first dose.

Discussion

A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be safe and 95% effective against Covid-19. The vaccine met both primary efficacy endpoints, with more than a 99.99% probability of a true vaccine efficacy greater than 30%. These results met our prespecified success criteria, which were to establish a probability above 98.6% of true vaccine efficacy being greater than 30%, and greatly exceeded the minimum FDA criteria for authorization.9 Although the study was not powered to definitively assess efficacy by subgroup, the point estimates of efficacy for subgroups based on age, sex, race, ethnicity, body-mass index, or the presence of an underlying condition associated with a high risk of Covid-19 complications are also high. For all analyzed subgroups in which more than 10 cases of Covid-19 occurred, the lower limit of the 95% confidence interval for efficacy was more than 30%.

The cumulative incidence of Covid-19 cases over time among placebo and vaccine recipients begins to diverge by 12 days after the first dose, 7 days after the estimated median viral incubation period of 5 days,10 indicating the early onset of a partially protective effect of immunization. The study was not designed to assess the efficacy of a single-dose regimen. Nevertheless, in the interval between the first and second doses, the observed vaccine efficacy against Covid-19 was 52%, and in the first 7 days after dose 2, it was 91%, reaching full efficacy against disease with onset at least 7 days after dose 2. Of the 10 cases of severe Covid-19 that were observed after the first dose, only 1 occurred in the vaccine group. This finding is consistent with overall high efficacy against all Covid-19 cases. The severe case split provides preliminary evidence of vaccine-mediated protection against severe disease, alleviating many of the theoretical concerns over vaccine-mediated disease enhancement.11

The favorable safety profile observed during phase 1 testing of BNT162b24,8 was confirmed in the phase 2/3 portion of the trial. As in phase 1, reactogenicity was generally mild or moderate, and reactions were less common and milder in older adults than in younger adults. Systemic reactogenicity was more common and severe after the second dose than after the first dose, although local reactogenicity was similar after the two doses. Severe fatigue was observed in approximately 4% of BNT162b2 recipients, which is higher than that observed in recipients of some vaccines recommended for older adults.12 This rate of severe fatigue is also lower than that observed in recipients of another approved viral vaccine for older adults.13 Overall, reactogenicity events were transient and resolved within a couple of days after onset. Lymphadenopathy, which generally resolved within 10 days, is likely to have resulted from a robust vaccine-elicited immune response. The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).

This trial and its preliminary report have several limitations. With approximately 19,000 participants per group in the subset of participants with a median follow-up time of 2 months after the second dose, the study has more than 83% probability of detecting at least one adverse event, if the true incidence is 0.01%, but it is not large enough to detect less common adverse events reliably. This report includes 2 months of follow-up after the second dose of vaccine for half the trial participants and up to 14 weeks’ maximum follow-up for a smaller subset. Therefore, both the occurrence of adverse events more than 2 to 3.5 months after the second dose and more comprehensive information on the duration of protection remains to be determined. Although the study was designed to follow participants for safety and efficacy for 2 years after the second dose, given the high vaccine efficacy, ethical and practical barriers prevent following placebo recipients for 2 years without offering active immunization, once the vaccine is approved by regulators and recommended by public health authorities. Assessment of long-term safety and efficacy for this vaccine will occur, but it cannot be in the context of maintaining a placebo group for the planned follow-up period of 2 years after the second dose. These data do not address whether vaccination prevents asymptomatic infection; a serologic endpoint that can detect a history of infection regardless of whether symptoms were present (SARS-CoV-2 N-binding antibody) will be reported later. Furthermore, given the high vaccine efficacy and the low number of vaccine breakthrough cases, the potential establishment of a correlate of protection has not been feasible at the time of this report.

This report does not address the prevention of Covid-19 in other populations, such as younger adolescents, children, and pregnant women. Safety and immune response data from this trial after immunization of adolescents 12 to 15 years of age will be reported subsequently, and additional studies are planned to evaluate BNT162b2 in pregnant women, children younger than 12 years, and those in special risk groups, such as immunocompromised persons. Although the vaccine can be stored for up to 5 days at standard refrigerator temperatures once ready for use, very cold temperatures are required for shipping and longer storage. The current cold storage requirement may be alleviated by ongoing stability studies and formulation optimization, which may also be described in subsequent reports.

The data presented in this report have significance beyond the performance of this vaccine candidate. The results demonstrate that Covid-19 can be prevented by immunization, provide proof of concept that RNA-based vaccines are a promising new approach for protecting humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with a sufficient investment of resources. The development of BNT162b2 was initiated on January 10, 2020, when the SARS-CoV-2 genetic sequence was released by the Chinese Center for Disease Control and Prevention and disseminated globally by the GISAID (Global Initiative on Sharing All Influenza Data) initiative. This rigorous demonstration of safety and efficacy less than 11 months later provides a practical demonstration that RNA-based vaccines, which require only viral genetic sequence information to initiate development, are a major new tool to combat pandemics and other infectious disease outbreaks. The continuous phase 1/2/3 trial design may provide a model to reduce the protracted development timelines that have delayed the availability of vaccines against other infectious diseases of medical importance. In the context of the current, still expanding pandemic, the BNT162b2 vaccine, if approved, can contribute, together with other public health measures, to reducing the devastating loss of health, life, and economic and social well-being that has resulted from the global spread of Covid-19.

Supported by BioNTech and Pfizer.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Polack and Thomas contributed equally to this article.

This article was published on December 10, 2020, and updated on December 16, 2020, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank all the participants who volunteered for this study; and the members of the C4591001 data and safety monitoring board for their dedication and their diligent review of the data. We also acknowledge the contributions of the C4591001 Clinical Trial Group (see the Supplementary Appendix); Tricia Newell and Emily Stackpole (ICON, North Wales, PA) for editorial support funded by Pfizer; and the following Pfizer staff: Greg Adams, Negar Aliabadi, Mohanish Anand, Fred Angulo, Ayman Ayoub, Melissa Bishop-Murphy, Mark Boaz, Christopher Bowen, Salim Bouguermouh, Donna Boyce, Sarah Burden, Andrea Cawein, Patrick Caubel, Darren Cowen, Kimberly Ann Cristall, Michael Cruz, Daniel Curcio, Gabriela Dávila, Carmel Devlin, Gokhan Duman, Niesha Foster, Maja Gacic, Luis Jodar, Stephen Kay, William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie-Pierre Hellio Le Graverand-Gastineau, Jacqueline Lowenberg, Rod MacKenzie, Robert Maroko, Jason McKinley, Tracey Mellelieu, Farheen Muzaffar, Brendan O’Neill, Jason Painter, Elizabeth Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick, Balaji Prabu Raja, Christine Rainey, Kellie Lynn Richardson, Elizabeth Rogers, Melinda Rottas, Charulata Sabharwal, Vilas Satishchandran, Harpreet Seehra, Judy Sewards, Helen Smith, David Swerdlow, Elisa Harkins Tull, Sarah Tweedy, Erica Weaver, John Wegner, Jenah West, Christopher Webber, David C. Whritenour, Fae Wooding, Emily Worobetz, Xia Xu, Nita Zalavadia, Liping Zhang, the Vaccines Clinical Assay Team, the Vaccines Assay Development Team, and all the Pfizer colleagues not named here who contributed to the success of this trial. We also acknowledge the contributions of the following staff at BioNTech: Corinna Rosenbaum, Christian Miculka, Andreas Kuhn, Ferdia Bates, Paul Strecker, Ruben Rizzi, Martin Bexon, Eleni Lagkadinou, and Alexandra Kemmer-Brück; and the following staff at Polymun: Dietmar Katinger and Andreas Wagner.

Author Affiliations

From Fundacion INFANT (F.P.P.) and iTrials-Hospital Militar Central (G.P.M.), Buenos Aires; State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (J.A., A.G., K.A.S., K.K., W.V.K., D.C., P.R.D., K.U.J., W.C.G.) — both in New York; Vaccine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., P.L.) and Worldwide Safety, Safety Surveillance and Risk Management (S.M.), Pfizer, Collegeville, PA; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and Centro Paulista de Investigação Clinica, São Paulo (C.Z.) — both in Brazil; Global Product Development, Pfizer, Peapack, NJ (S.R.); Cincinnati Children’s Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health, Baltimore (L.L.H.); BioNTech, Mainz (ÖT., U.Ş.), and Medizentrum Essen Borbeck, Essen (A.S.) — both in Germany; Tiervlei Trial Centre, Karl Bremer Hospital, Cape Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety, Safety Surveillance and Risk Management, Pfizer, Groton, CT (D.B.T.).

Address reprint requests to Dr. Absalon at Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, or at judith.absalon@pfizer.com.

A complete list of investigators in the C4591001 Clinical Trial Group is provided in the Supplementary Appendix, available at NEJM.org.

Supplementary Material

ProtocolPDF4781KB
Supplementary AppendixPDF171KB
Disclosure FormsPDF559KB
Data Sharing StatementPDF71KB
Research SummaryPDF3161KB

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Citing Articles (954)

Letters
Figures/Media
  1. Download a PDF of the Research Summary.
  2. Figure 1. Enrollment and Randomization. The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.
  3. Table 1. Demographic Characteristics of the Participants in the Main Safety Population.*
  4. Figure 2. Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel A. Pain at the injection site was assessed according to the following scale: mild, does not interfere with activity; moderate, interferes with activity; severe, prevents daily activity; and grade 4, emergency department visit or hospitalization. Redness and swelling were measured according to the following scale: mild, 2.0 to 5.0 cm in diameter; moderate, >5.0 to 10.0 cm in diameter; severe, >10.0 cm in diameter; and grade 4, necrosis or exfoliative dermatitis (for redness) and necrosis (for swelling). Systemic events and medication use are shown in Panel B. Fever categories are designated in the key; medication use was not graded. Additional scales were as follows: fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild: does not interfere with activity; moderate: some interference with activity; or severe: prevents daily activity), vomiting (mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; or severe: requires intravenous hydration), and diarrhea (mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; or severe: 6 or more loose stools in 24 hours); grade 4 for all events indicated an emergency department visit or hospitalization. 𝙸 bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.
  5. Table 2. Vaccine Efficacy against Covid-19 at Least 7 days after the Second Dose.*
  6. Table 3. Vaccine Efficacy Overall and by Subgroup in Participants without Evidence of Infection before 7 Days after Dose 2.
  7. Figure 3. Efficacy of BNT162b2 against Covid-19 after the First Dose. Shown is the cumulative incidence of Covid-19 after the first dose (modified intention-to-treat population). Each symbol represents Covid-19 cases starting on a given day; filled symbols represent severe Covid-19 cases. Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point. The time period for Covid-19 case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for vaccine efficacy (VE) is derived according to the Clopper–Pearson method.

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